Over the past 20 years, while deaths attributed to hypertensive vascular disease have declined in the United States, the incidence of end-stage renal disease (ESRD) associated with hypertension has increased1. Moreover, the presence of even early stage nephropathy is an independent risk factor for development of cardiovascular events2. Therefore, slowing progression of kidney disease is an important factor to consider when selecting antihypertensive medications for patients with kidney disease and proteinuria.
Proteinuria is a sensitive and independent predictor for the progression of nephropathy and cardiovascular disease3,4,5,6,7,8. Several clinical studies have shown that higher levels of proteinuria are associated with increased progression of renal and cardiovascular disease and that reductions in proteinuria are associated with a decrease in the rate of renal function deterioration and cardiovascular events4,5,6,7,9. As a result of this relationship, proteinuria is frequently used as a surrogate end point in clinical research studies assessing the effects of antihypertensive agents on the progression of renal disease5.
Reductions in blood pressure have been associated with decreases in both urine protein excretion and the progression of nephropathy in patients with chronic kidney disease4,8,10,11,12. Both the angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to have these effects12,13,14,15,16. However, the evidence for the renoprotective effects of calcium antagonists is more equivocal. This is exemplified by the results of prospective randomized trials where, in spite of similar levels of blood pressure, nephropathy progression was faster and proteinuria higher in the group randomized to a dihydropyridine calcium antagonist (DCA) compared to a blocker of the renin-angiotensin system (RAS)12,14,16.
A number of studies have suggested that the dihydropyridine and nondihydropyridine subclasses of calcium antagonists may have differential effects on proteinuria and the progression of renal disease11,12,16,17,18,19. In an earlier systematic review by Kloke et al, the authors concluded that calcium antagonists are effective antihypertensive drugs, but there was uncertainty about the renal benefits of these medications in patients with proteinuric renal disease and renal insufficiency5. In several studies, dihydropyridine calcium antagonists (DCAs) were not shown to reduce proteinuria or slow the progression of renal insufficiency9,11,12,18,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36. In a limited number of studies, data suggested that nondihydropyridine calcium antagonists (NDCAs) may provide beneficial effects on kidney function19,37,38,39,40,41. However, data from an adequately powered clinical trial are needed to reach a conclusion regarding the ability of NDCAs to reduce proteinuria and slow nephropathy progression.
The purpose of this systematic review was to evaluate data from recent clinical studies to determine the differential effects of calcium antagonists on renal outcomes as measured by changes in proteinuria. The primary objective was to assess whether DCAs and NDCAs have differential effects on proteinuria in hypertensive adults with or without diabetes.
METHODS
Data sources
Multiple sources were used to obtain published and unpublished data relevant to this systematic review. Computerized databases, including MEDLINE, PubMed, Internet Grateful Med, Library of the National Medical Society, Find Articles, and EMBASE, were searched using key words and index terms to identify relevant published articles Table 1. The references from these articles were reviewed to identify additional clinical trials. In addition, governmental agencies, medical organizations, thought leaders, and pharmaceutical companies that manufacture a calcium antagonist were contacted to identify additional studies, with either negative or positive outcomes that should be considered for inclusion in the systematic review. It should be noted that no additional substantive data beyond that of the published literature was produced using these sources. All studies considered for this review were documented. From the 139 abstracts screened, 47 full-text articles were retrieved, and 20% (28/139) were included in the review9,11,12,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41. Criteria for study selection are described below.
Table 1 - Key words and index terms used to identify articles for inclusion in the review.
Full table Study selection
Summary data was obtained from 28 randomized, controlled trials assessing the effects of calcium antagonists on renal end points in hypertensive patients with and without diabetes. In order to be included in the review, studies had to be designed as a randomized clinical trial with a duration of at least 6 months of treatment; had to include a DCA or NDCA treatment arm; had to have 1 or more renal end points (e.g., proteinuria, glomerular filtration rate [GFR], creatinine level, ESRD, or dialysis); and had to have been initiated after 1986. This cut-off date was chosen for two reasons. Prior to 1986, proteinuria was not used as an end point in any controlled, randomized trials of the effects calcium antagonists on renal function, and after this date, a highly sensitive radioimmunoassay became the most commonly used technique for measuring urine protein42. Twenty-eight studies were included in this systematic review. Twenty-one studies included DCA treatment groups, six included NDCA treatment groups, and 1 included both Table 2. Five studies included treatment arms with combination therapy of calcium antagonists and ACE inhibitors.
In the systematic review process, the validity or quality of each study included in the review must be measured. However, the authors recognized that this approach is inherently subjective and has been the subject of some controversy43,44,45. As a result, an assessment of the methodologic quality of each study in this review was completed by instituting strict selection criteria that were specific to the design of the study. Because the selection criteria were objective, a single individual assessed the quality of each study. This individual was blinded to the outcome of the study in order to minimize selection bias. These criteria were employed to ensure inclusion only of studies with high methodological quality with respect to the study design. Studies that were relevant to the clinical goals of the review but did not meet the selection criteria were excluded from further consideration.
Data extraction
Several individuals received training on the process of abstracting data for the systematic review in order to minimize interextractor variability. Each individual received training on how to use the electronic data collection form and an equivalent term dictionary. These individuals were divided into two teams that independently reviewed all of the articles included in the systematic review. Each team entered information into identical but separate electronic databases. In situations where data was not available from published sources, the corresponding author was contacted whenever possible to obtain the missing data. After the data were abstracted from the articles, the data in the two databases were compared to identify discrepancies.
A third team of independent reviewers evaluated each discrepancy. The reviewers compared the disparate data to the original article and made a final determination concerning which data to accept. An audit log was maintained of all changes to the database. The two original independent databases were locked and archived for analysis of interextractor variability. Interextractor agreement was 97%, whereas tertiary verification led to error-free rates of 100% for primary data fields and 99% for the secondary data fields.
Study outcomes
The primary end point of this review was the percentage change in proteinuria from baseline in patients treated with DCAs or NDCAs. Proteinuria is a widely accepted surrogate end point for the progression of renal disease in studies of antihypertensive agents. In addition, proteinuria was expected to occur more frequently than ESRD or other renal outcomes, providing higher statistical power for analysis using this measure. Secondary end points included effect of DCAs and NDCAs on ending proteinuria values, systolic blood pressure, diastolic blood pressure, and mean arterial pressure (MAP). Progression of nephropathy was defined as an increase in proteinuria in spite of blood pressure reduction or worsening of renal function relative to the comparator defined as either an increase of greater than 50% in serum creatinine or a 25% reduction in GFR, if measured.
Study characteristics
Summary-level data were extracted from published articles for 28 randomized trials that assessed the effects of calcium antagonists and other antihypertensive agents on the progression of renal disease. The characteristics of the patients evaluated in these studies were considered to be sufficiently similar to justify pooling the data for an aggregate analysis. With the exception of 15 patients included in the study by Schnack et al34, all patients were hypertensive (blood pressure greater than 140/90 mm Hg), and all patients had decreased renal function.
Statistical analysis
The studies included in the review followed different protocols, requiring standardization of variable definitions for the purpose of analysis. Measures of urine protein (excluding albumin) were recorded in mg/day. Based on the accepted estimation that 40% of total urine protein is albumin, urine albumin measurements were converted to urine protein values by dividing by 0.446. MAP was calculated by adding the systolic blood pressure reading plus two times the diastolic blood pressure reading, divided by three.
The SAS® (SAS Institute, Inc., Cary, NC, USA) software program was used for all statistical analyses. Clinical and demographic characteristics of each treatment group were summarized with means and standard deviations (SD) or percentages and were presented for groups treated with DCA or NDCA and with and without diabetes. In order to evaluate the treatment effects of the calcium antagonists, studies that included combination treatment arms were not used for the primary analysis.
Treatment groups were compared in terms of the percentage change from baseline values while adjusting for sample size. The effect of treatment duration on proteinuria could not be assessed without individual patient data, and comparisons of end values were also adjusted for duration of treatment. Both end points were evaluated with analysis of covariance (ANCOVA) using each study as an experimental unit. The assumptions of ANCOVA were confirmed, and no interactions between the covariates were found. In addition, ANCOVA techniques were used to compare diabetic groups on proteinuria end points and to compare the treatment groups on the blood pressure end points. All P values were based on two-sided tests, and significance was set at P < 0.05.
Summary tables were compiled from study data reported for the 28 trials included in the review. As a result, the statistical methods used to analyze summary data from these articles treated each study as an independent observation unit in the analysis.
RESULTS
Blood pressure parameters were analyzed for 1338 patients from 22 studies. The baseline characteristics were not significantly different between the 1338 patients included in the analysis and the 235 patients excluded because of missing values. Both classes of calcium antagonists decreased mean systolic and diastolic blood pressure Table 3. After adjusting for sample size, study length, and baseline value, there was no statistically significant difference in blood pressure reduction between the classes.
Table 3 - Effects of dihydropyridine calcium antagonists (DCAs) and nondihydropyridine calcium antagonists (NDCAs) (monotherapy) on blood pressure parameters.
Full table Twenty-three studies had both baseline and end-of-study proteinuria levels documented. As a result, 510 patients contributed data for this analysis. The baseline characteristics were not significantly different between the 510 patients included in the analysis and the 1081 patients excluded because of missing values. The baseline, end-of-study, and change in proteinuria values are shown in Table 4. A 32% difference in proteinuria values was observed between the two subclasses. There was +2% change in proteinuria for DCAs and -30% change for NDCAs (95% CI, 10% to 54%, P < 0.01) Figure 1. There were consistently greater reductions in proteinuria associated with the use of NDCAs than with the use of DCAs, despite no statistically significant differences in blood pressure between the groups.
Figure 1.
The change in proteinuria and systolic blood pressure. The percentage change in proteinuria, after adjustment for sample size and study length, for dihydropyridine calcium antagonists (DCAs) and nondihydropyridine calcium antagonists (NDCAs) was 2% and -30%, respectively (P < 0.01). The percentage change in systolic blood pressure, after adjustment for sample size and study length, for DCAs and NDCAs was -13% and -18.5%, respectively (P = 0.28).
Full figure and legend (10K)Table 4 - Effects of dihydropyridine calcium antagonists (DCAs) and dihydropyridine calcium antagonists (NDCAs) (monotherapy) on proteinuria in patients with renal disease, by study.
Full table In order to assess the effect of reductions in blood pressure on proteinuria levels with DCA or NDCA treatment, an analysis was completed that adjusted for sample size, study length, and change in systolic blood pressure. A 27% mean change in proteinuria was observed between the two calcium antagonist subclasses. There was +1% change in proteinuria for DCAs and -26% change for NDCAs (95% CI, -8% to 63%, P = 0.16) Table 5. Although not statistically significant, these results suggested that the trend demonstrating greater reductions in proteinuria associated with the use of NDCAs compared with DCAs persisted after adjusting for changes in blood pressure. A possible explanation for the lack of statistical significance for this analysis is that there were fewer studies that documented both baseline and end-of-study blood pressure and proteinuria values, resulting in low statistical power.
Table 5 - Estimated changes in proteinuria among patients treated with dihydropyridine calcium antagonists (DCAs) or nondihydropyridine calcium antagonists (NDCAs) (monotherapy) adjusted for sample size, study length, and blood pressure parameters.
Full table A secondary analysis that included data for calcium antagonists as monotherapy and in combination with ACE inhibitors or ARBs showed the mean change in proteinuria was 2% for DCAs and -39% for NDCAs (95% CI for a 41% difference, 19% to 63%, P = 0.002) Table 6. These findings suggest that NDCAs alone or in combination with an ACE inhibitor or ARB produced significant reductions in proteinuria, whereas DCAs did not demonstrate an antiproteinuric effect.
Table 6 - Effects of dihydropyridine calcium antagonists (DCAs) and nondihydropyridine calcium antagonists (NDCAs) [monotherapy or with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARB) on proteinuria in patients with renal disease, by studya.
Full table As a result of this differential effect of DCAs and NDCAs on proteinuria, NDCAs were expected to reduce the progression of renal disease whereas DCAs were not. However, an analysis of this end point was inconclusive because of the limited number of studies involving NDCAs included in this review. In addition, this review was performed using summary data rather than individual patient data, and the relationship between calcium antagonists and renal disease progression could not be fully assessed.
There were also no statistically significant differences in proteinuria or blood pressure parameters in patients with or without diabetes in any of the studies. As a result, no further analysis of diabetic patients by treatment was undertaken.
The sensitivity of the aggregate results was evaluated by assessing the impact of each individual study on the pooled results in order to determine whether the observed effects of the DCAs and NDCAs were affected by inclusion of any of the clinical trials. The analysis was schematically repeated, excluding each study in turn, to identify which studies were most influential on the results. Because only seven studies included a NDCA, it was expected that the results would be somewhat sensitive. However, the direction of the results and the magnitude of the effects were expected to remain stable.
The sensitivity analysis revealed that the study by Smith, Toto, and Bakris17, when removed from the analysis, was most influential in reducing the magnitude of the treatment effect (+2% for DCAs and -26% for NDCAs, P = 0.038)17. The study by Preston et al39 was the most influential in increasing the magnitude of the treatment effect when removed from the analysis (+1% for DCAs and -36% for NDCAs, P = 0.004). All steps in the sensitivity analysis showed a significant differential effect on proteinuria between the DCAs and NDCAs. In addition, the magnitude of the effect remained stable. Therefore, the aggregate results of this review were not sensitive to the inclusion or exclusion of any individual study.
DISCUSSION
It has been established that calcium antagonists are effective for reducing blood pressure in patients with renal failure who are considered to be relatively resistant to antihypertensive treatment5. This benefit is consistent with the results from this review. According to this analysis, both DCAs and NDCAs equally reduced blood pressure. There were no significant differences in any of the blood pressure parameters after treatment. This is further supported by outcomes data from large trials such as the Irbesartan Diabetic Nephropathy Trial (IDNT) and the African American Study of Kidney Disease and Hypertension (AASK) trials as well as other studies, which show a strong association between reductions in proteinuria and slower declines in kidney function11,12,15,16. In the trials, a DCA (amlodipine) failed to reduce proteinuria, an effect that correlated with a faster decline in kidney function, despite substantial reductions in blood pressure.
However, an analysis of the studies included in this review suggested that a differential effect exists between DCAs and NDCAs on proteinuria, despite equal reductions in systemic blood pressure. This analysis showed that there were consistently greater reductions in proteinuria with the use of NDCAs, either alone or in combination with an ACE inhibitor or ARB, compared with DCAs. This trend persisted after adjusting for changes in blood pressure. This trend also remained unchanged for both diabetic and nondiabetic renal disease and differing levels of proteinuria.
The differential effect of DCAs and NDCAs on proteinuria has been studied in several animal models, and in one human study17,47,48,49. This differential effect could be caused by a variety of factors, including differences in the ability of DCAs and NDCAs to affect renal autoregulation, glomerular permeability, and tubular protein reabsorption.
Results from animal studies suggested that DCAs, through their action on the afferent arteriole, markedly attenuate the autoregulatory ability of the kidney to alter GFR over a wide range of arterial pressures. This would result in linear transmission of the systemic blood pressure to the glomerular capillary47,48,49, and hence, an increase in intraglomerular pressure, unless blood pressure was markedly reduced to levels well below 120 mm Hg48. Glomerular hypertension also results in increased protein filtration, albuminuria, and endothelial damage, leading to the release of soluble mediators that promote replacement of normal kidney tissue by fibrosis47,48,49. As a result, the beneficial effects of blood pressure reduction seen with DCAs are overcome by the increased transmission of pressure into the glomerulus due to sustained afferent vasodilatation5. In experimental studies, NDCAs also interfere with renal autoregulation, although they do not totally ablate this process48. This differential effect from DCAs may be related, in part, to the effects of NDCAs on efferent as well as afferent arteriolar tone50,51,52. Additionally, NDCAs, unlike DCAs, reduce glomerular permeability9,17,25,53; this effect on permeability coupled with the partial preservation of renal autoregulation by NDCAs translate into decreases in albuminuria and preservation of renal morphology47,48,49.
These differential effects on glomerular permeability are also described in clinical studies, with one study demonstrating a unique effect of DCAs to block tubular protein reabsorption17,49,54. However, this would only account for a small change in protein not albumin and would not be unique to the DCAs. In human studies of diabetic nephropathy, NDCAs were shown to reduce glomerular membrane permeability, especially to large molecules17,49. This results in decreased albumin filtration, proteinuria, and endothelial damage, that is associated with reduced progression of nephrosclerosis55,56. These differences in membrane permeability are not directly related to blood pressure lowering17,49.
Taken together, these mechanistic differences may explain the differential effect of DCAs and NDCAs on proteinuria observed in this review. Further data from large outcome trials is needed in humans to assess these hypothesized explanations.
It is well documented that antihypertensive agents that fail to reduce proteinuria in patients with nephropathy also fail to maximally alter progression of renal disease8,11,16,49,57. This suggests that reductions in both blood pressure and proteinuria are necessary to reduce nephropathy progression in patients with proteinuria12,58,59,60,61.
In two randomized, double-blind studies of patients with advanced nephropathy and proteinuria, IDNT and AASK, DCAs, in the absence of agents that block the RAS, failed to reduce proteinuria levels and to slow the progression of nephropathy, despite achieving reductions in blood pressure comparable to that achieved with an ACE inhibitor or ARB. In contrast, controlled clinical trials of NDCAs have consistently shown reductions in both blood pressure and proteinuria, and the use of NDCAs in participants with advanced diabetic nephropathy have been shown to slow the progression of renal disease in small studies with long-term follow-up19,37,38,39,40,41. Based on the results of controlled clinical trials that demonstrated an association between a reduction in blood pressure and proteinuria and a slowing of the progression of renal disease, the results of this review support the suggestion that NDCAs may be superior to DCAs in reducing the progression of nephropathy.
Because DCAs have not demonstrated as beneficial as blockers of the RAS on the progression of kidney disease, they should not be considered a first-line treatment in patients with kidney disease who have proteinuria. Conversely, NDCAs, alone or in combination with an ACE inhibitor or an ARB, should be considered over DCAs alone for treating hypertensive patients with nephropathy and proteinuria. A recent post hoc analysis of the Reduction of End Points in Type 2 Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) trial, however, shows that DCAs when used with an ARB do not abrogate the benefits of the ARB for slowing nephropathy progression57. Further, because ESRD and cardiovascular morbidity and mortality are clinically important outcomes of renal disease progression, an analysis of these outcomes should be incorporated into future comparative studies of the renoprotective effects of calcium antagonists. Such studies will provide valuable insight into the therapeutic advantages of using calcium antagonists in conjunction with antihypertensives in the treatment of renal disease.
The findings of this review have both clinical and economic implications for health care providers. In a recent cost analysis using United States Renal Data Service (USRDS) data, costs associated with the treatment of ESRD have been estimated at approximately $66,000 United States dollars per patient per year62. The worldwide cost is estimated to be between $70 and $75 billion United States dollars. The use of medications with renal protective properties can significantly reduce health care costs associated with renal disease. Herman et al recently performed a cost analysis of the RENAAL study and estimated that the ARB generated a net savings of $3555 United States dollars per patient over 3.5 years in treatment costs for ESRD63. Therefore, antihypertensive agents with documented renal protective properties can improve clinical outcomes while reducing health care costs.
Limitations of the study
A meta-analysis was originally planned in order to more fully assess the differential effect of DCAs and NDCAs on blood pressure, and proteinuria. In order to assess these effects, all of the studies included in the meta-analysis had to have included treatment arms with both DCAs and NDCAs. However, only 1 study included in the review met this criterion. As a result, a differential effect between DCAs and NDCAs could not be assessed with meta-analytical techniques. Instead, a systematic review was conducted.
In addition, this review was performed using summary data rather than individual patient data. As a result, the unit of observation was the study and not the patient. Therefore, the statistical power of the analysis was lower than it would have been with an analysis of the individual patient data. The nonsignificant difference between groups in terms of systolic and diastolic blood pressure and MAP did not necessarily mean that groups were similar; a lack of data could also account for this lack of difference. However, even with the reduction in power caused by using the study as the unit of analysis, there was compelling evidence to support the findings that DCAs and NDCAs differentially affect proteinuria while having no significant difference in their effect on blood pressure.
CONCLUSION
This analysis supports the following conclusions: (1) there was no statistically significant difference between DCAs and NDCAs in their effect on blood pressure parameters; (2) NDCAs are superior to DCAs in reducing proteinuria, despite no statistically significant difference in the blood pressure–lowering effects of these two subclasses; and (3) the antiproteinuric superiority of NDCAs was evident in both diabetic and nondiabetic renal disease. Based on the findings of this systematic review and the fact that proteinuria levels correlate with higher risk of kidney failure and cardiovascular events8,64,65,66. NDCAs, alone or in combination with an ACE inhibitor or an ARB, should be preferred over DCAs for treating hypertensive patients with proteinuric renal disease or renal insufficiency.
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Acknowledgments
This analysis was funded with the help of an unrestricted grant from Abbott Laboratories, The review was independently conducted and reported by the employees of ACCESS Medical Group, Ltd., under the direction of the principal author, none of whom have any financial interest with Abbott Laboratories. The authors wish to thank the following people for their assistance with data analysis: Stephen L. Apple, M.D., Peter Kusel, Ph.D., Lisa M. Aubey, Oliver Fultz, and Stacey C. Tobin, Ph.D.
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